The present invention relates to a process for producing piperidinecarboylic acid amide derivatives useful as serotonin antagonists, antithrombocytic agents or intermediates for them.
Ischemic diseases such as myocardial infarction and cerebral infarction are concerned with thrombi. In particular, it is considered that thrombocytes play an important part in the formation of thrombosis in the arteries. Thus, various antithrombocytic agents were developed. For example, Japanese Patent Unexamined Published Application (hereinafter referred to as xe2x80x9cJ. P. KOKAIxe2x80x9d) No. Hei 8-3135 reported compounds usable as the serotonin antagonists or antithrombocytic agents. The following process for producing compounds having a piperidinecarboxylic acid amide structure, among those compounds, is disclosed therein. 
However, 2-aminoethyl bromide used in this process is a poisonous substance, and carcinogenic aziridine is possible to be formed by the reactions. Thus, this process is not preferred for the production on an industrial scale. Under these circumstances, the development of a safer process has been demanded.
The object of the present invention is to provide an industrially excellent process for producing piperidinecarboxylic acid amide derivatives.
Another object of the present invention is to provide new piperidinecarboxylic acid amide derivatives.
Other objects of the present invention will be apparent from the following descriptions and Examples.
After intensive investigations, the inventors have found that the above-described piperidinecarboxylic acid amide derivatives can be obtained safely in a high yield under relatively mild conditions by reacting a 2-oxazoline compound with a piperidine derivative, which is a precursor of the intended compound, in the presence of an acid. The present invention has been completed on the basis of this finding.
Namely, the present invention provides a process for producing piperidinecarboxylic acid amide derivatives of general formula (9), which comprises the step of reacting a 2-oxazoline compound of general formula (1) with a piperidine derivative of general formula (2) or a salt thereof in the presence of an acid: 
wherein X represents a heterocyclic ring which may have a substituent, an alkyl group having 1 to 10 carbon atoms, which may have a substituent, an alkoxyl group having 1 to 10 carbon atoms, which may have a substituent, a cycloalkyl group having 3 to 10 carbon atoms, which may have a substituent, an alkenyl group having 2 to 10 carbon atoms, which may have a substituent, an aralkyl group having 7 to 12 carbon atoms and having an alkyl moiety having 1 to 6 carbon atoms, which may have a substituent, or phenyl group 
wherein Y represents hydrogen atom or a halogen atom, and Z represents an organic group of any of the following formulae (3), (4), (5), (6), (7) and (8), 
wherein X, Y and Z are as defined above.
The present invention also provides piperidinecarboxylic acid amide derivatives of the following general formula (10): 
X in general formula (1) for the 2-oxazoline compounds used in the present invention is a heterocyclic ring which may have a substituent, an alkyl group having 1 to 10 carbon atom, which may have a substituent, an alkoxyl group having 1 to 10 carbon atom, which may have a substituent, a cycloalkyl group having 3 to 10 carbon atom, which may have a substituent, an alkenyl group having 2 to 10 carbon atom, which may have a substituent, or an aralkyl group having 7 to 12 carbon atoms and having an alkyl moiety having 1 to 6 carbon atoms, which may have a substituent, or phenyl group.
The heterocyclic rings include, for example, pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, piperazyl, thienyl and furyl groups.
The alkyl groups having 1 to 10 carbon atoms may be either linear or branched, and they include, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl groups.
The alkoxyl groups having 1 to 10 carbon atoms may be either linear or branched, and they include, for example, methoxyl, ethoxyl, propoxyl, butoxyl, pentyloxy, hexyloxy, heptyloxy and octyloxy groups.
The cycloalkyl groups having 3 to 10 carbon atoms include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl groups.
The alkenyl groups having 2 to 10 carbon atoms may be either linear or branched, and they include, for example, ethylene, propylene, butene, pentene, hexene, heptene, octene, nonene and decene groups.
In the aralkyl groups having 7 to 12 carbon atoms and also having an alkyl moiety having 1 to 6 carbon atoms, the alkyl moiety may be either linear or branched. They include, or example, phenylmethyl, phenylethyl, phenylpropyl, henylbutyl, phenylpentyl and phenylhexyl groups.
These groups X may be either substituted or substituted. When X is a phenyl group, heterocyclic group or cycloalkyl group, the substitution position on the ring is not particularly limited, and the substituent may be any of the above-described alkyl, alkoxyl and alkenyl groups.
2-Oxazoline compounds of general formula (1) can be easily produced by, for example, a process described in Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 82, p. 2032 (1960). For example, 2-(1-formyl-4-piperidino)-2-oxazoline can be produced by reacting an amido compound (prepared from 1-formylisonipecotic acid and 2-aminoethanol) with p-toluenesulfonyl chloride under basicconditions. 2-Methyl-4,5-dihydo-1,3-oxazole of general formula (1) wherein X is methyl group and 2-ethyl-4,5-dihydo-1,3-oxazole of general formula (1) wherein X is ethyl group are easily available on the market on relatively low cost.
In general formula (2) for the piperidine derivatives used in the present invention, Y represents hydrogen atom or a halogen atom, and Z represents an organic group of any of following formulae (3) to (8): 
The piperidine derivatives of general formula (2) are known compounds described in Journal of Medicinal Chemistry, Vol. 8, p. 829 (1965) and J. P. KOKAI Nos. Sho 50-18478, Hei 3-12835, Hei 5-208976, etc. They can be easily produced by methods described in J. P. KOKAI Nos. Hei 3-128354 and Hei 5-208976. For example, 4-(5H--dibenzo[a,d]cycloheptene-5-ylidene)-1-piperidine can be obtained by reacting 4-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-1-methylpiperidine with ethyl chloroformate or the like to replace the methyl group with ethoxycarbonyl group or the like and then eliminating the ethoxycarbonyl group or the like with, for example, potassium hydroxide.
As for the acids usable in the present invention, the Lewis acids include, for example, BF.(CH3CH2)2O and zinc chloride, and the proton acids include, for example, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid and nitric acid. Among them, p-toluenesulfonic acid or its hydrate is the most preferred for inhibiting the production of by-products and for obtaining the intended product in a high yield. The amount of the acid used herein is in a relatively wide range. It is preferably 3 to 75 molar %, more preferably 4 to 70 molar %, still more preferably 6 to 60 molar %, further preferably 5 to 50 molar %, particularly preferably 8 to 25 molar %, and most preferably 10 to 17 molar %. When it is smaller than 5 molar %, the reaction yield is lowered and, on the contrary, more than 100 molar % of the acid is economically not preferred and the reaction yield is lowered in such a case.
The reaction temperature in the present invention, which varies depending on the kind of the starting materials, kind of the solvent and other conditions, is usually 50 to 140xc2x0 C., preferably 70 to 130xc2x0 C. and still preferably 80 to 125xc2x0 C. At a high temperature of above 140xc2x0 C., a pressure vessel is necessitated because of the gasification of the starting materials and solvent and, on the contrary, a temperature of below 50xc2x0 C. is not preferred for conducting the reaction on an industrial scale because the reaction rate is seriously lowered.
The reaction solvents usable in the present invention include halogenated hydrocarbons such as chloroform and carbon tetrachloride; aromatic hydrocarbons such s benzene, toluene and xylene; and hydrocarbons such as heptane and hexane. Water and alcohols are not preferred because they cause the decomposition of 2-oxazoline. The reaction can be conducted without any solvent.
The reaction product obtained by the process of the present invention is isolated and purified in the form of the free compound or a salt thereof. The isolation/purification can be conducted by the extraction, concentration, distillation, crystallization and various chromatographic methods.
Some of the piperidinecarboxylic acid amide derivatives of general formula (9) produced by the process of the present invention are known to be usable as the serotonin antagonists or antithrombocytic agents according to, for example, J. P. KOKAI No. Hei 8-3135. For example, J. P. KOKAI No. Hei 8-3135 discloses compounds of general formula (9) wherein Y is either hydrogen atom or a halogen atom, Z is an organic group of any of following formulae (3), (4), (6) and (8): 
and X is a heterocyclic ring which may have a substituent (preferably pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazyl group which may have a substituent), an alkyl group having 1 to 8 carbon atoms and a substituent, a cycloalkyl group having 4 to 8 carbon atoms and a substituent, or an alkoxyl group having 1 to 8 carbon atoms which may have a substituent. According to J. P. KOKAI No. Hei 8-3135, the substituent of X is preferably a substituent of either following formula (11) or (12): 
wherein R2 represents a hydrogen atom, an alkyl or alkoxyl group having 1 to 6 carbon atoms, or an amino or acylaminoalkyl group which may be substituted with an alkyl group, and R3 and R4, which may be the same or different from each other, each represent a hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having 1 to 6 carbon atoms, or an aminocarbonyl group which may be substituted with an alkyl group.
Examples of the substituents of X include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-xcex2-alanyl, N-acetyl-xcex2-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl and N-ethyl-N-acetyl groups.
When Z is an organic group of formula (5) or (7) and X is an alkenyl group having 2 to 10 carbon atoms and a substituent, an aralkyl group having 7 to 12 carbon atoms, a substituent and an alkyl moiety having 1 to 6 carbon atoms, or phenyl group, examples of the substituents of X are the same as those described above.
The compounds which per se are known to be usable as the serotonin antagonists or antithrombocytic agents as described above can be easily produced by the one-step reaction according to the process of the present invention.
On the other hand, piperidinecarboxylic acid amides of above general formula (9), but which are different from those described above, are useful as intermediates for the serotonin antagonists or antithrombocytic agents. Namely, compounds of above general formula (9) wherein X represents a substituent-free alkyl group having 1 to 10 carbon atoms, a substituent-free cycloalkyl group having 3 to 10 carbon atoms, a substituent-free alkenyl group having 2 to 10 carbon atoms, a substituent-free aralkyl group having 7 to 12 carbon atoms and an alkyl moiety having 1 to 6 carbon atoms, or phenyl group (preferably a substituent-free alkyl group having 1 to 10 carbon atoms, particularly preferably, a substituent-free alkyl group having 1 to 3 carbon atoms) are usable as the intermediates for the serotonin antagonists or antithrombocytic agents. When such a compound is used as the intermediate, a piperidinecarboxylic acid amide derivative of general formula (9) is hydrolyzed with an acid, such as 10% aqueous sulfuric acid solution, to obtain a compound of general formula (13), and this compound is condensed with a carboxylic acid derivative of X such as 1-formylisonicopetic acid (14) to obtain a piperidinecarboxylic acid amide derivative, such as that represented by general formula (15), useful as the serotonin antagonist or antithrombocytic agent. 
Wherein X, Y and Z are as defined above.
When the intended product is obtained via the intermediate as described above, the intermediate is particularly preferably a piperidinecarboxylic acid derivative of following general formula (10) because they can be easily synthesized from 2-oxazoline compounds available on the market: 
Wherein R1 represents methyl or ethyl group, and Y and Z are as defined above.
In the production of the piperidinecarboxylic acid amide derivatives included in the compounds of general formula (9) and useful as the serotonin antagonists or antithrombocytic agents, the method of producing the intended compound can be suitably selected from two methods, i.e. the above-described method wherein substituent X is introduced through the intermediate, and the method wherein substituent X is previously introduced into the 2-oxazoline compound and the intended product is directly produced by the one-step reaction.
In the present invention, piperidinecarboxylic acid amide derivative of general formula (9) usable as the serotonin antagonist or antithrombocytic agent is produced by the one-step reaction, then this derivative can be used as an intermediate and another substituent is introduced thereinto by the above-described method to obtain a serotonin antagonist or antithrombocytic agent having another function.